Controlling Pharmaceutical Crystallization with Designed Polymeric Heteronuclei

Abstract

To investigate the hypothesis that molecules acting as crystallization inhibitors in solution could be transformed into crystallization promoters, additives were synthesized that mimic the pharmaceuticals acetaminophen and mefenamic acid and also possess polymerizable functionality. It was found that, in solution, these additives face-selectively inhibit crystal growth and lead to overall slower crystal appearance. In contrast, when the tailor-made additives were incorporated into an insoluble polymer, the induction time for the onset of crystal formation for both pharmaceuticals was substantially decreased. This approach now allows for the synthesis of tailor-made polymers that decrease the induction time for crystal appearance and may find application in compounds that are resistant to crystallization or in improving the fidelity of heteronucleation approaches to solid form discovery.

Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization

“…Heterogeneous crystallization involves nucleation onto an existing surface, which decreases the effects of molecular conformations and the solvent, while providing a surface as a template [ 70 , 71 , 72 ]. This has historically been used through the practice of “seeding” the crystallization process, where pre-formed crystals of the desired polymorphs are introduced to the supersaturated drug solution so that additional nuclei orient into the same crystal structure [ 73 , 74 ].…”

Synthesis and Functionalization of Nanoparticles in Supercritical CO2

“…These methods have some disadvantages which include the size of particles that cannot be properly controlled in the non-sized range, but using of some additives (excipients, surfactants, etc.) can produce the stabilization nanocrystals or nanoparticles regarding the morphological properties and the crystallized polymorphic form [2]. Bottom-up techniques showed some advantages because they are low-energy processes and less expensive than the other methods, and obtained particles have narrow size distribution.…”

Enantiomer-selective magnetization of conglomerates for quantitative chiral separation

“…Undoubtedly, selective crystallization is still the most economical and convenient method to provide large-scale chiral compounds 8 . Through 170-year development of this method, several sub-strategies have been developed, i.e., spontaneous crystallization 9 , diastereomer crystallization 10,11 , preferential crystallization 12 (including heteronucleation assisted by nanoparticles 13,14 ) and tailor-made additives for selective inhibition 15–17 , etc. Some of these strategies are quite sophisticated in providing mass optically pure enantiomers through multiple-cycle crystallization assisted by complex industrial setups.…”